Rationale: Severe respiratory syncytial virus bronchiolitis has been associated with deficient interferon- production in humans but the role of this cytokine in determining the outcome of reinfection is unknown. Objectives: To define the role of interferon- in the development of respiratory syncytial virusmediated airway hyperresponsiveness and lung histopathology in mice. Methods: Wild-type and interferon- knockout mice were infected with respiratory syncytial virus in the newborn or weaning stages and re-infected five weeks later. Airway responses were assessed on day 6 after the primary or secondary infection. Measurements and Main Results: Both wild-type and interferon- knockout mice developed similar levels of airway hyperresponsiveness and airway inflammation after primary infection. Following re-infection, interferon- knockout mice, but not wild-type mice, developed airway hyperresponsiveness, airway eosinophilia, and mucus hyperproduction. Intranasal administration of interferon- during primary infection but not during re-infection prevented the development of these altered airway responses on re-infection in interferon- knockout mice. Adoptive transfer of wild-type T cells into interferon- knockout mice prior to primary infection restored interferon- production in the lungs and prevented the development of altered airway responses on reinfection. Treatment of mice with interferon- during primary neonatal infection prevented the enhancement of airway hyperresponsiveness and the development of airway eosinophilia and mucus hyperproduction on re-infection. Conclusions: Interferon- production during primary respiratory syncytial virus infection is critical to the development of protection against airway hyperresponsiveness and lung histopathology on re-infection. Provision of interferon- during primary infection in infancy may be a potential therapeutic approach to alter the course of respiratory syncytial virus-mediated long-term sequelae.